Vps34 regulates myofibril proteostasis to prevent hypertrophic cardiomyopathy.
Vps34 regulates myofibril proteostasis to prevent hypertrophic cardiomyopathy.
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DOI：
10.1172/jci.insight.89462
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发表时间：
2017-01
期刊：
影响因子：
8
通讯作者：
H. Kimura;S. Eguchi;J. Sasaki;K. Kuba;H. Nakanishi;S. Takasuga;Masakazu Yamazaki;A. Goto;Hiroyuki Watanabe;H. Itoh;Y. Imai;A. Suzuki;N. Mizushima;Takehiko Sasaki
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作者：
H. Kimura;S. Eguchi;J. Sasaki;K. Kuba;H. Nakanishi;S. Takasuga;Masakazu Yamazaki;A. Goto;Hiroyuki Watanabe;H. Itoh;Y. Imai;A. Suzuki;N. Mizushima;Takehiko Sasaki
肥厚型心肌病（HCM）是一种常见的心脏病，在一般人群中的患病率为1/500。在HCM患者中发现了编码心脏蛋白的基因的几种突变，但这些变化不能预测HCM的发生或预后，HCM的分子机制仍然很难解释。在这里，我们表明，心脏表达的空泡蛋白分选34（Vps 34）减少HCM患者的一个子集。在小鼠模型中，肌肉特异性Vps 34丢失导致HCM样表现和猝死。Vps 34缺陷型心脏表现出异常的组织病理学，包括肌原纤维紊乱和含有α B-晶体蛋白（CryAB）的聚集体。这些特征是由ESCRT介导的蛋白水解中的阻断引起的，该蛋白水解通常降解K63-聚泛素化CryAB。CryAB沉积也发现在心肌标本从一个子集的HCM患者的心脏显示降低的Vps 34。我们的研究结果确定了以前未知的Vps 34-CryAB轴的破坏作为HCM的潜在新病因。
Hypertrophic cardiomyopathy (HCM) is a common heart disease with a prevalence of 1 in 500 in the general population. Several mutations in genes encoding cardiac proteins have been found in HCM patients, but these changes do not predict occurrence or prognosis and the molecular mechanisms underlying HCM remain largely elusive. Here we show that cardiac expression of vacuolar protein sorting 34 (Vps34) is reduced in a subset of HCM patients. In a mouse model, muscle-specific loss of Vps34 led to HCM-like manifestations and sudden death. Vps34-deficient hearts exhibited abnormal histopathologies, including myofibrillar disarray and aggregates containing αB-crystallin (CryAB). These features result from a block in the ESCRT-mediated proteolysis that normally degrades K63-polyubiquitinated CryAB. CryAB deposition was also found in myocardial specimens from a subset of HCM patients whose hearts showed decreased Vps34. Our results identify disruption of the previously unknown Vps34-CryAB axis as a potentially novel etiology of HCM.